Although PD is predominated by motor symptoms (tremor, rigidity and bradykinesia) during its initial stages, with disease progression the majority of patients develop additional non-motor manifestations like cognitive impairment, psychiatric complications and autonomic dysfunction. Among the most common are visual hallucinations seen in about 1/3 of PD patients. Visual hallucinations are usually related to L-dopa therapy, significantly influence quality of life and lead to increased mortality in PD. Although their clinical variables have been somewhat defined, their neurochemical basis remains unknown. Lack of such knowledge limits therapeutic efficacy in PD and may compromise the development and use of future therapies like stem cell transplantation and nerve growth factor gene transfer. This project focuses on the characterization of the neurochemical changes leading to visual hallucinations in PD. We propose that these symptoms result from a complex process that involves accumulation of the protein alpha-synuclein and dysregulation of DAergic pathways affecting the ventral tegmental area (VTA), to later extend to the ventral striatal (nucleus accumbens) and mesocorticolimbic regions (amygdala). To this end, we will evaluate the neurodegenerative process as well as key components of the DAergic system in these regions. We propose three specific objectives to address these issues: 1) To characterize the expression of alpha-synuclein in the substantia nigra, vental tegmental area and striatum using immunocytochemistry, immunoblotting, and in situ hybridization techniques in postmortem brain specimens of PD patients with and without visual halluinations as well as age-matched controls. 2) To map and visualize the loss of DAergic projections to the limbic target areas by determining the expression of dopamine transporter (DAT) binding and 3) To examine the regulation of D1, D2 and D3 DAergic receptors using autoradiographic binding techniques in limbic brain regions in PD. Our long term objective is to identify neurochemical mechanisms related to the development of drug-induced psychotic symptoms in PD. This Small Grant (R03) application from a new investigator is concentrated in obtaining key pilot data on the etiopathogenesis of visual hallucinations (VH) in Parkinson's disease. Recent publications from our group, our preliminary results, the brain tissue availability and the multidisciplinary team assembled provide strong support for the feasibility of this project. [unreadable] [unreadable] [unreadable]